The long-term objective of this proposal is to determine the molecular basis of hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) through identification and characterization of the gene for this autosomal dominant disorder associated with recurrent painful brachial plexus dysfunction. Individuals with HNA may suffer repeated episodes of intense pain, paralysis and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for ' recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). The biochemical and molecular basis of HNA is unknown. The gene for HNA has been finely mapped to chromosome 17q25 with few pedigrees showing genetic heterogeneity. Standard methods of human linkage analysis will be used to identify additional HNA pedigrees, refine the location of the HNA gene on chromosome 17q25, test candidate genes and, if necessary, isolate a gene for HNA through positional cloning methods. Genetic and physical methods will be used to narrow the region of the HNA locus to a 1-megabase interval. Many candidate genes have been identified, and sequencing is in progress to identify mutations leading to HNA. Identification of the HNA gene will permit the assessment of its patterns of tissue distribution and developmental expression in addition to providing novel insights into the molecular and biochemical abnormalities leading to both the HNA phenotype. Moreover, characterization of the HNA gene may have broader pathophysiological and therapeutic implications for more common idiopathic forms of brachial neuropathy. [unreadable] [unreadable]